Effect of "Zhibian" (BL 54)-to-"Shuidao" (ST 28) needle insertion on the expression of Fas/FADD/Caspase-8 of death receptor pathway in rats with primary ovarian insufficiency / 中国针灸

OBJECTIVE@#To explore the effect of "Zhibian" (BL 54)-to-"Shuidao" (ST 28) needle insertion on the ovarian function in the rats with primary ovarian insufficiency (POI) and the potential effect mechanism based on the Fas/FADD/Caspase-8 of death receptor pathway.@*METHODS@#Forty-eight female SD rats were randomly divided into a blank group, a model group, a medication group and an acupuncture group, with 12 rats in each group. Except in the blank group, the rats in the other groups were intraperitoneally injected with cyclophosphamide to establish the POI model. In the acupuncture group, after successful modeling, the intervention was given with "Zhibian" (BL 54)-to- "Shuidao" (ST 28) needle insertion, once daily, 30 min in each intervention; and the duration of intervention was 4 weeks. In the medication group, estradiol valerate tablets were administered intragastrically, 0.09 mg•kg-1•d-1, for 4 weeks. The general situation and the estrous cycle of the rats were compared among groups. Using ELISA, the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and estradiol (E2) in the serum were detected. HE staining was adopted to observe the morphological changes of ovarian tissue of rats. The protein expression of Fas, FADD and Caspase-8 in ovarian tissue was detected with immunohistochemistry and Western blot.@*RESULTS@#After modeling, except the rats of the blank group, the rats of the other groups had dry fur, lost hair, low spirits, reduced food intake, increased urination and loose stool. After intervention, the stool became regular gradually in the acupuncture group and the medication group. The percentage of estrous cycle disturbance was increased in the rats of the model group when compared with the blank group (P<0.01); in comparison with the model group, the percentages of estrous cycle disturbance were reduced in the acupuncture group and the medication group after intervention (P<0.01). When compared with the blank group, the body mass and E2 content in the serum were lower (P<0.01), the levels of FSH and LH in the serum and the protein expression levels of Fas, FADD and Caspase-8 were increased (P<0.01) in the model group. Compared with the model group, the body mass and E2 contents in the serum were higher (P<0.01), the levels of FSH and LH in the serum and the protein expression levels of Fas, FADD and Caspase-8 were reduced (P<0.01) in the acupuncture group and the medication group.@*CONCLUSION@#"Zhibian" (BL 54)-to-"Shuidao" (ST 28) needle insertion can effectively improve the ovarian function of POI rats, and its effect mechanism may be related to regulating the serum sex hormone levels, reducing the expression of Fas, FADD and Caspase-8 in ovarian tissue and retarding apoptosis of ovarian cells.

Analysis of PD-L1 expression in salivary duct carcinoma with its efficacy as a tumor marker / 대한두경부종양학회지

BACKGROUND/OBJECTIVES: Despite multiple approaches of treatments for salivary duct carcinoma, there has been a need for more successful treatment methods because of its poor prognosis. Treatment options like immunotherapy using new technologies have been attempted. Based on recent study results indicating that targeting programmed death receptors are effective in treating various cancers, this study aimed to identify the frequency of PD-L1 expression and its impact on survival rate in salivary duct carcinoma.MATERIALS #SPCHAR_X0026; METHODS: We studied 33 patients with salivary gland cancer who were available for histologic specimens. We examined the expression of PD-L1 in the tissues and analyzed the association with the survival rate and the association with various clinical parameters.RESULTS: According to this study and review of similar studies, we discovered that the expression of PD-L1 in salivary duct carcinoma was lower than other types of cancers. The impact of PD-L1 on survival rate also showed inconsistency in salivary duct carcinoma.CONCLUSION: Immunotherapy by PD-1/PD-L1 checkpoint blockade in salivary duct carcinoma needs further evaluation for clinical application.

Involvement of Up-regulation of Death Receptors and Bim in Hispolon-mediated TNF-related Apoptosis-inducing Ligand Sensitization in Human Renal Carcinoma

BACKGROUND: Hispolon has been shown to possess antitumor effects in various cancer cells. However, the underlying mechanisms are not fully understood. In this study, we evaluated the sensitizing effect of hispolon on TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis in human renal carcinoma cells. METHODS: Apoptosis was analyzed by using cell-based cytometer. The mRNA levels were assessed by reverse transcription-PCR. Bax activation was determined by oligomerization and fluorescence-activated cell sorting with Bax-NT monoclonal antibody. The protein expression was measured by Western blotting. RESULTS: Hispolon induced up-regulation of Bim and death receptors expression at the post-translational level. CONCLUSIONS: Hispolon enhanced TRAIL-mediated apoptosis in renal carcinoma cells, but not in normal cells.

Induction of Apoptosis Scutellaria baicalensis Georgi Root Extract by Inactivation of the Phosphatidyl Inositol 3-kinase/Akt Signaling Pathway in Human Leukemia U937 Cells

BACKGROUND: The roots of Scutellaria baicalensis Georgi (Labiatae) have been widely used in traditional medicine for treatment of various diseases. In this study, we investigated the effects of ethanol extracts of S. baicalensis roots (EESB) on the growth ofn human leukemia U937 cells. METHODS: The effect of EESB on cell viability was measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide assay. Apoptosis was determined using 4,6-diamidino-2-phenyllindile staining and flow cytometry. The effects of EESB on the expression of regulatory proteins of apoptosis and phosphatidyl inositol 3-kinase (PI3K)/Akt signaling were determined by Western blotting. Caspase activity and mitochondrial membrane potential (MMP) were measured using flow cytometric analysis.

Therapeutic Effects of Synthetic Antimicrobial Peptides, TRAIL and NRP1 Blocking Peptides in Psoriatic Keratinocytes / 전남의대학술지

Psoriasis is a chronic, recurrent, heterogeneous, cutaneous inflammatory skin disease for which there is no cure. It affects approximately 7.5 million people in the United States. Currently, several biologic agents that target different molecules implicated in the pathogenic processes of psoriasis are being assessed in diverse clinical studies. However, relapse usually occurs within weeks or months, meaning there is currently no cure for psoriasis. Therefore, recent studies have discovered diverse new potential treatments for psoriasis: inhibitors of bacteria such as Staphylococcus aureus, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and neuropilin 1 (NRP1). A promising approach that has recently been described involves modifying antimicrobial peptides to develop new cutaneous anti-bacterial agents that target inflammatory skin disease induced by Staphylococcus. Increased expression of TRAIL and its death receptors DR4 and DR5 has been implicated in the pathogenesis of plaque psoriasis. In addition, TRAIL has the ability to inhibit angiogenesis by inducing endothelial cell death and by negative regulation of VEGF-induced angiogenesis via caspase-8-mediated enzymatic and non-enzymatic functions. Since NRP1 regulates angiogenesis induced by multiple signals, including VEGF, ECM and semaphorins, and also initiates proliferation of keratinocytes through NF-κB signaling pathway in involved psoriatic skin, targeting NRP1 pathways may offer numerous windows for intervention in psoriasis. In this review, we will focus on the current knowledge about the emerging role of synthetic antimicrobial peptides, TRAIL and NRP1 blocking peptides in the pathogenesis and treatment of psoriasis.

Anti-Proliferative Activities of Vasicinone on Lung Carcinoma Cells Mediated via Activation of Both Mitochondria-Dependent and Independent Pathways

Vasicinone, a quinazoline alkaloid from Adhatoda vasica Nees. is well known for its bronchodilator activity. However its antiproliferative activities is yet to be elucidated. Here-in we investigated the anti-proliferative effect of vasicinone and its underlying mechanism against A549 lung carcinoma cells. The A549 cells upon treatment with various doses of vasicinone (10, 30, 50, 70 µM) for 72 h showed significant decrease in cell viability. Vasicinone treatment also showed DNA fragmentation, LDH leakage, and disruption of mitochondrial potential, and lower wound healing ability in A549 cells. The Annexin V/PI staining showed disrupted plasma membrane integrity and permeability of PI in treated cells. Moreover vasicinone treatment also lead to down regulation of Bcl-2, Fas death receptor and up regulation of PARP, BAD and cytochrome c, suggesting the anti-proliferative nature of vasicinone which mediated apoptosis through both Fas death receptors as well as Bcl-2 regulated signaling. Furthermore, our preliminary studies with vasicinone treatment also showed to lower the ROS levels in A549 cells and have potential free radical scavenging (DPPH, Hydroxyl) activity and ferric reducing power in cell free systems. Thus combining all, vasicinone may be used to develop a new therapeutic agent against oxidative stress induced lung cancer.

Extracellular acidity enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis via DR5 in gastric cancer cells

The tumor microenvironment greatly influences cancer cell characteristics, and acidic extracellular pH has been implicated as an essential factor in tumor malignancy and the induction of drug resistance. Here, we examined the characteristics of gastric carcinoma (GC) cells under conditions of extracellular acidity and attempted to identify a means of enhancing treatment efficacy. Acidic conditions caused several changes in GC cells adversely affecting chemotherapeutic treatment. Extracellular acidity did inhibit GC cell growth by inducing cell cycle arrest, but did not induce cell death at pH values down to 6.2, which was consistent with down-regulated cyclin D1 and up-regulated p21 mRNA expression. Additionally, an acidic environment altered the expression of atg5, HSPA1B, collagen XIII, collagen XXAI, slug, snail, and zeb1 genes which are related to regulation of cell resistance to cytotoxicity and malignancy, and as expected, resulted in increased resistance of cells to multiple chemotherapeutic drugs including etoposide, doxorubicin, daunorubicin, cisplatin, oxaliplatin and 5-FU. Interestingly, however, acidic environment dramatically sensitized GC cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Consistently, the acidity at pH 6.5 increased mRNA levels of DR4 and DR5 genes, and also elevated protein expression of both death receptors as detected by immunoblotting. Gene silencing analysis showed that of these two receptors, the major role in this effect was played by DR5. Therefore, these results suggest that extracellular acidity can sensitize TRAIL-mediated apoptosis at least partially via DR5 in GCs while it confers resistance to various type of chemotherapeutic drugs.

The role of necroptosis in neurosurgical diseases

Programmed necrosis or necroptosis is an alternative form of cell death that is executed through a caspase-independent pathway. Necroptosis has been implicated in many pathological conditions. Genetic or pharmacological inhibition of necroptotic signaling has been shown to confer neuroprotection after traumatic and ischemic brain injury. Therefore, the necroptotic pathway represents a potential target for neurological diseases that are managed by neurosurgeons. In this review, we summarize recent advances in the understanding of necroptotic signaling pathways and explore the role of necroptotic cell death in craniocerebral trauma, brain tumors, and cerebrovascular diseases.

Anti-tumor activities and apoptotic mechanism of ribosome-inactivating proteins / 癌症

Ribosome-inactivating proteins (RIPs) belong to a family of enzymes that attack eukaryotic ribosomes and potently inhibit cellular protein synthesis. RIPs possess several biomedical properties, including anti-viral and anti-tumor activities. Multiple RIPs are known to inhibit tumor cell proliferation through inducing apoptosis in a variety of cancers, such as breast cancer, leukemia/lymphoma, and hepatoma. This review focuses on the anti-tumor activities of RIPs and their apoptotic effects through three closely related pathways: mitochondrial, death receptor, and endoplasmic reticulum pathways.

p53-dependent Fas expression is critical for Ginsenoside Rh2 triggered caspase-8 activation in HeLa cells

We have recently reported that Ginsenoside Rh2 (G-Rh2) induces the activation of two initiator caspases, caspase-8 and caspase-9 in human cancer cells. However, the molecular mechanism of its death-inducing function remains unclear. Here we show that G-Rh2 stimulated the activation of both caspase-8 and caspase-9 simultaneously in HeLa cells. Under G-Rh2 treatment, membrane death receptors Fas and TNFR1 are remarkably upregulated. However, the induced expression of Fas but not TNFR1 was contributed to the apoptosis process. Moreover, significant increases in Fas expression and caspase-8 activity temporally coincided with an increase in p53 expression in p53-non-mutated HeLa and SK-HEP-1 cells upon G-Rh2 treatment. In contrast, Fas expression and caspase-8 activity remained constant with G-Rh2 treatment in p53-mutated SW480 and PC-3 cells. In addition, siRNA-mediated knockdown of p53 diminished G-Rh2-induced Fas expression and caspase-8 activation. These results indicated that G-Rh2-triggered extrinsic apoptosis relies on p53-mediated Fas over-expression. In the intrinsic apoptotic pathway, G-Rh2 induced strong and immediate translocation of cytosolic BAK and BAX to the mitochondria, mitochondrial cytochrome c release, and subsequent caspase-9 activation both in HeLa and in SW480 cells. p53-mediated Fas expression and subsequent downstream caspase-8 activation as well as p53-independent caspase-9 activation all contribute to the activation of the downstream effector caspase-3/-7, leading to tumor cell death. Taken together, we suggest that G-Rh2 induces cancer cell apoptosis in a multi-path manner and is therefore a promising candidate for anti-tumor drug development.

Bcl-2 Knockdown Accelerates T Cell Receptor-Triggered Activation-Induced Cell Death in Jurkat T Cells

Cell death and survival are tightly controlled through the highly coordinated activation/inhibition of diverse signal transduction pathways to insure normal development and physiology. Imbalance between cell death and survival often leads to autoimmune diseases and cancer. Death receptors sense extracellular signals to induce caspase-mediated apoptosis. Acting upstream of CED-3 family proteases, such as caspase-3, Bcl-2 prevents apoptosis. Using short hairpin RNAs (shRNAs), we suppressed Bcl-2 expression in Jurkat T cells, and this increased TCR-triggered AICD and enhanced TNFR gene expression. Also, knockdown of Bcl-2 in Jurkat T cells suppressed the gene expression of FLIP, TNF receptor-associated factors 3 (TRAF3) and TRAF4. Furthermore, suppressed Bcl-2 expression increased caspase-3 and diminished nuclear factor kappa B (NF-kappaB) translocation.

Expression of death cellular receptors FAS/CD95 and DR4 during porcine placentation / Expresión de los receptores de muerte celular FAS/CD95 y DR4 durante la placentación porcina

Apoptosis is a permanent and dynamic physiological process by which an organism eliminates the undesirable cells without causing an inflammatory response. The objective of this work was to study the expression of FAS, DR4 and other members of the TNF-R1 superfamily extrinsic route apoptotic receptors the DNA fragmentation and the cellular apoptosis in placental samples at the early, mid and late pregnancy on +/- 30, +/- 55 and +/- 114 gestational days, respectively. We used placental histological sections of samples fixed in buffered saline formaldehyde. Immunohistochemical techniques were performed to detect the apoptotic receptors, whereas the DNA fragmentation was detected by TUNEL reaction and apoptotic cellular ultrastructure was detected by TEM conventional techniques. Apoptosis related receptors were immunolocalized in the early pig gestation and correlated with apoptosis, suggesting a role in the cellular remodelling of the placenta. At gestation day 55, apoptosis might be correlated to FAS route, but not by DR4-mediating pathway. At the end of gestation, increased apoptosis and both receptors markers were detected showing cellular death due to the extrinsic route through FAS and DR4 receptors. In conclusion, the immunolocalization of FAS and TNF R-1 receptors along the pig placental development correlates with TUNEL reaction and with apoptotic ultrastructure observed by TEM and seems to occur through different pathways along gestation.

La apoptosis es un proceso fisiológico, dinámico y permanente a través del cual un organismo elimina células indeseables sin provocar una respuesta inflamatoria. El objetivo del presente trabajo fue estudiar la expresión de los receptores de la vía extrínseca de apoptosis, FAS, DR4 y otros miembros de la superfamilia TNF-R1, la fragmentación del ADN y la apoptosis celular a través de TEM, en muestras placentarias del inicio, la mitad y el final de la gestación, hacia el día +/- 30, +/- 55 y +/- 114 de preñez, respectivamente. Se realizaron cortes histológicos de las muestras placentarias fijadas en formol tamponado. Para la detección de los receptores de apoptosis se realizaron técnicas inmunohistoquímicas, para el estudio de la fragmentación del ADN se utilizó el ensayo TUNEL y para el análisis de la ultraestructura celular apoptótica la técnica convencional de TEM. La inmunolocalización de los receptores de muerte celular al inicio de la preñez porcina sugiere el rol de la apoptosis en la remodelación celular placentaria. Hacia el día 55 de preñez, la apoptosis detectada ocurriría únicamente a través de la vía del receptor FAS, no del receptor DR4. Al final de la gestación, se detectó un incremento de la apoptosis y la expresión de ambos receptores, indicando que la muerte celular a través de la vía de señalización extrínseca estaría inducida por los receptores FAS y DR4. En conclusión, la inmunolocalización de los receptores FAS y otros miembros del TNF-R1, los resultados de TUNEL y la ultraestructura celular apoptótica observada en la placentación porcina, indican que la apoptosis detectada ocurre por diferentes vías de inducción a lo largo de la gestación.

Eosinophil Survival and Apoptosis in Health and Disease

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders.

Eosinophil Survival and Apoptosis in Health and Disease

Eosinophilia is common feature of many disorders, including allergic diseases. There are many factors that influence the production, migration, survival and death of the eosinophil. Apoptosis is the most common form of physiological cell death and a necessary process to maintain but limit cell numbers in humans and other species. It has been directly demonstrated that eosinophil apoptosis is delayed in allergic inflammatory sites, and that this mechanism contributes to the expansion of eosinophil numbers within tissues. Among the proteins known to influence hematopoiesis and survival, expression of the cytokine interleukin-5 appears to be uniquely important and specific for eosinophils. In contrast, eosinophil death can result from withdrawal of survival factors, but also by activation of pro-apoptotic pathways via death factors. Recent observations suggest a role for cell surface death receptors and mitochondria in facilitating eosinophil apoptosis, although the mechanisms that trigger each of these death pathways remain incompletely delineated. Ultimately, the control of eosinophil apoptosis may someday become another therapeutic strategy for treating allergic diseases and other eosinophil-associated disorders.

Cardiomyocyte apoptosis and death receptor pathway in a rat model of coronary microembolization / 中华心血管病杂志

<p><b>OBJECTIVE</b>To investigate the dynamic changes of cardiomyocyte apoptosis and the role of death receptor apoptotic pathway in a rat model of coronary microembolization (CME).</p><p><b>METHODS</b>Adult rats were randomized to coronary microembolization (CME group, n = 63) or sham-operated group (S group, n = 55). CME model was established by aortic injection of 0.1 ml microspheres (42 microm, 3 x 10(4)/ml) into the left ventricle when the ascending aorta was temporarily clamped.S group received 0.1 ml saline injection and survived rats were randomly examined at 0, 3, 6, 12 and 24 hour post CME (n = 10 each). Heart function was evaluated by echocardiography. Myocardium sample was stained with hematoxylin-eosin and hematoxylin-basic fuchsin-picric acid to detect infarct areas. Cardiomyocyte apoptosis was detected with TUNEL staining. The expression of caspase-3 and caspase-8 was measured by Western blot analysis.</p><p><b>RESULTS</b>Compared with S group, the left ventricular ejection fraction was significantly decreased and left ventricular end-diastolic diameter was significantly increased in CME group (all P < 0.05) except 0 hour CME group. The infarct sizes were similar in 3 hour, 6 hour, 12 hour, and 24 hour CME groups (P > 0.05). The apoptosis index (AI) in CME group were significantly higher at each time point compared to S group (P < 0.05) except 0 hour CME group and peaked at 6 hours. Apoptotic cardiomyocytes were found mainly in the myocardial microinfarcted area and border zones. The relative expression of caspase-3 and caspase-8 in CME group were both significantly increased at 3 hours and peaked at 6 hour post CME (P < 0.05).</p><p><b>CONCLUSION</b>Cardiomyocytes apoptosis was significantly increased after coronary microembolization via activating death receptor apoptotic pathway in this coronary microembolization model.</p>

Immunohistochemical Analysis for the Expression of DR5 TRAIL Receptor and p53 in Non-small Cell Lung Cancer / 결핵및호흡기질환

BACKGROUND: TRAIL is a promising anticancer agent which induces selective tumor cell death due to a unique receptor system that includes death receptors and decoy receptors. DR5 TRAIL receptor is an originally identified p53-regulated death receptor gene that was induced, by doxorubicine, only in cells with a wild-type p53 status. We investigated that focused on the correlation between the DR5 and p53 expressions in non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical analysis, with using avidin-biotinylated horseradish peroxidase complex, was carried out in 89 surgically resected NSCLC formalin-fixed paraffin-embedded tissue sections. As primary antibodies, we used anti-DR5 polyclonal antibody and anti-p53 monoclonal antibody. A negative control was processed with each slide. The positive tumor cells were quantified twice and these values were expressed as percentage of the total number of tumor cells, and the intensity of immunostaining was expressed. The analysis of the DR5 expression was done separately in tumor area and in a nearby region of normal tissue. RESULTS: The DR5 expression was high in the bronchial epithelium (89% of cases) but this was almost absent in type I & II pneumocytes, lymphocytes and smooth muscle cells. High DR5 expression rate in tumor was seen in 28% (15/53) of squamous cell carcinomas, in 47% (15/32) of adenocarcinomas and, in 50% (2/4) of large cell carcinomas. The DR5 expression did not show any statistical significance relationship with the T stage, N stage, or survival. However, the DR5 expression showed significant inverse correlation with the p53 expression. (p<0.01). CONCLUSION: We demonstrated that the DR5 expression in NSCLC via immunohistochemical analysis is relatively tumor-specific except for that in the normal bronchial epithelium and it is significantly dependent on the p53 status. This might be in vivo evidence for the significance of the DR5 gene as a p53 downstream gene.

Apoptosis: from signaling pathways to therapeutic tools

Apoptosis or programmed cell death is a gene regulated phenomenon which is important in both physiological and pathological conditions. It is characterized by distinct morphological features including chromatin condensation, cell and nuclear shrinkage, membrane blebbing and oligonucleosomal DNA fragmentation. Although, two major apoptotic pathways including 1] the death receptor [extrinsic] and 2] mitochondrial [intrinsic] pathway have been identified, recently endoplasmic reticulum and lysosomal pathways have been also recognized. Depending on both the cell type and the initiating factor, distinct pathways are activated. The pathways share a common final phase of apoptosis, consisting of activation of the executioner caspases and dismantling of substrates critical for cell survival. The important regulatory mechanisms include death receptors, caspases, mitochondria and Bcl-2 family proteins. Modulating of apoptosis is a novel therapeutic strategy in treatment of different diseases. These include situations with unwanted cell accumulation [cancer] and failure to diminish aberrant cells [autoimmune diseases] or diseases with an inappropriate cell loss [heart failure, stroke, AIDS and neurodegenerative diseases]. Modulation of apoptosis is a novel therapeutic strategy in treatment of different diseases. Many approaches including gene therapy, antisense strategies and numerous apoptotic drugs to target specific apoptotic regulators, are currently being developed. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, signaling as well as a discussion of apoptosis in diseases and effective therapy

Apoptosis and progression of hepatic fibrosis in hepatitis C patients

Hepatitis C is a worldwide endemic disease, affecting roughly 200 million people. It has a variable prognosis, depending on the progression to fibrosis. During the last five years, the importance of apoptosis for the pathogenesis of various diseases, including hepatitis, has been recognized. It has been suggested that an increase in T cell-apoptosis during a hepatitis C virus infection is the cause of impaired regulation of the immune cellular response, helping to maintain infection. Thus, the interest in discovering the probable mechanisms by which the hepatitis C virus perpetuates in the liver, and to determine the conditions that predispose for progression of this disease, makes investigation of apoptosis in hepatic injury of great interest. We have made an overview of the various mechanisms by which the cell, more specifically the hepatic cell, is affected by apoptosis, and how it interacts with the hepatitis C virus and the immune system.

Trichostatin A induces apoptosis in lung cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway

Trichostatin A (TSA), originally developed as an antifungal agent, is one of potent histone deacetylase (HDAC) inhibitors, which are known to cause growth arrest and apoptosis induction of transformed cells, including urinary bladder, breast, prostate, ovary, and colon cancers. However, the effect of HDAC inhibitors on human non-small cell lung cancer cells is not clearly known yet. Herein, we demonstrated that treatment of TSA resulted in a significant decrease of the viability of H157 cells in a dose-dependent manner, which was revealed as apoptosis accompanying with nuclear fragmentation and an increase in sub-G0/G1 fraction. In addition, it induced the expression of Fas/FasL, which further triggered the activation of caspase-8. Catalytic activation of caspase-9 and decreased expression of anti-aptototic Bcl-2 and Bcl-XL proteins were observed in TSA-treated cells. Catalytic activation of caspase-3 by TSA was further confirmed by cleavage of pro-caspase-3 and intracellular substrates, including poly (ADP-ribose) polymerase (PARP) and inhibitor of caspase-activated deoxyribonuclease (ICAD). In addition, a characteristic phenomenon of mitochondrial dysfunction, including mitochondrial membrane potential transition and release of mitochondrial cytochrome c into the cytosol was apparent in TSA-treated cells. Taken together, our data indicate that inhibition of HDAC by TSA induces the apoptosis of H157 cells through signaling cascade of Fas/FasL-mediated extrinsic and mitocondria-mediated intrinsic caspases pathway.

Immunohistochemical Analysis of Fas-associated Death Domain Protein Expression in Stomach Cancers

PURPOSE: Evidence exists that dysregulation of apoptosis is involved in the pathogenesis of cancer development. Fas- associated death domain (FADD) protein, an adaptor protein of death receptors, is a critical regulatory component of the extrinsic cell- death pathway that exerts its pro-apoptotic effect upon binding with death receptors. Expression of the FADD protein has not been reported in stomach cancer. The aim of this study was to explore the expression status of the FADD protein in stomach cancers. MATERIALS AND METHODS: In the current study, we analyzed the expression of the FADD protein in 60 advanced stomach cancer by using immunohistochemistry and a tissue microarray approach. RESULTS: Immunopositivity (defined as > or =30%) was observed for the FADD protein in 23 (38%) of the 60 cancers. Normal gastric mucosal cells showed expression of the FADD protein. CONCLUSION: Taken together, these results indicate that decreased expression of the FADD protein is a frequent event in stomach cancers and suggest that to avoid apoptosis, stomach cancer cells in vivo may need loss of FADD expression, which might contribute to tumor development.